PROJECT SUMMARY Cardiovascular disease remains one of the leading causes of death in the world. Its progression is part of the aging process. From mouse to man, one consistent feature of aging and cardiovascular disease is the stiffening of blood vessels. This elastic property is tantamount to blood vessels to effectively deliver blood to target organs. With progressive stiffening, the consequence can be organ failure and death often as a consequence of heart attacks and strokes, which exhibit a unique timing, a circadian rhythm. Indeed, the molecular components of circadian rhythm?the circadian clock, including Bmal1, Clock, Per, and Cry, which we have shown are expressed and oscillating in blood vessels are intimately connected with the aging of blood vessels. In mice with circadian dysfunction (Bmal1-KO mice), we have discovered that there is increased vascular stiffness in their blood vessels, suggesting that a broken clock may speed the aging of blood vessels, and age-dependent worsening of pathological vascular remodeling. We have also found that the disintegrin/metalloprotease ADAM17/TACE tracks uniquely with age in human blood vessels, and that it exhibits a circadian rhythm as do its outputs including JAM-1/F11r, TNF, and IL6r. Moreover, we also demonstrate that Bmal1-KO mice exhibit increased levels of the cytokine outputs TNF and IL6, and in a microarray study find Bmal1-KO nave and transplanted vessels exhibit significant changes in ADAM17 targets. The central hypothesis of this application is that dysfunction of circadian clock is a prime mediator of age-related impairment of arterial relaxation and elasticity, which we propose is through ADAM17 regulation. Three Specific Aims are proposed. In Specific Aim 1 we will determine if a dysfunctional circadian clock mediates accelerated vascular dysfunction and arterial stiffening in aging. In Specific Aim 2, we will dissect the arterial wall-intrinsic and extrinsic mechanisms, which alter vascular clock and cause arterial stiffness in aging. In Specific Aim 3, we propose to examine the relationship between circadian clock dysfunction and ADAM17 activation in age-dependent vascular stiffening.